The long term objective of this research is the localization and characterization of genes important for Gilles de la Tourette syndrome (GTS) and related conditions. Recent research has led to several advances in our understanding of GTS and related conditions: 1) there is a greater range of phenotypic expression for GTS; 2) GTS and related disorders are much more common than had previously been thought; 3) there appear to be genes of major effect important for the manifestation of this condition and 4) a genome screen using affected sib-pairs suggests that there are at least two regions that may harbor susceptibility loci for GTS. The prevalence of GTS and associated illnesses and their debilitating effects on those afflicted makes these conditions a major public health problem. Understanding the genetics of GTS and associated behaviors will be of direct benefit to patients concerned about recurrence in their families; ultimately, clarifying the genetics of this condition may elucidate its pathogenesis. Previous studies completed by members of this group suggest that the mode of transmission of GTS and related disorders is consistent with the existence of genes that have a significant impact on the manifestation of GTS. Previous linkage studies in psychiatry employing large multigenerational families have been unsuccessful in locating genes important for the expression of neuropsychiatric disorders. Thus, we undertook an affected sib-pair genetic linkage study of GTS. A genome wide screen was completed using highly polymorphic markers 10cM apart and two highly suggestive genomic regions were identified. In the current application, we are proposing to collect an additional 200 affected sibpairs to follow-up these initial results. We will also follow-up all results in a sample of 30 large multigenerational families that have been studied for the past decade. Furthermore, DNA samples will be collected from GTS patients and their parents from both an admixed population and a genetic isolate in South Africa. A separate genome screen will be completed with the South African sample and compared to results from two studies examining Ashkenazi GTS patients and patients from an isolate in Costa Rica. Linkage disequilibrium studies will be utilized to more accurately localize and identify genes of interest. The long term goal of this work is to isolate and characterize genetic loci important in the manifestation of GTS. Phenotypic data will be obtained by direct structured psychiatric interview of all pertinent family members with respect to the occurrence of GTS and related conditions. Linkage and association analyses will be completed with state-of-the-art non-parametric methods.